8cn6
CD59 in complex with CP-06 peptide
Structural highlights
DiseaseCD59_HUMAN Defects in CD59 are the cause of CD59 deficiency (CD59D) [MIM:612300.[1] FunctionCD59_HUMAN Potent inhibitor of the complement membrane attack complex (MAC) action. Acts by binding to the C8 and/or C9 complements of the assembling MAC, thereby preventing incorporation of the multiple copies of C9 required for complete formation of the osmolytic pore. This inhibitor appears to be species-specific. Involved in signal transduction for T-cell activation complexed to a protein tyrosine kinase. The soluble form from urine retains its specific complement binding activity, but exhibits greatly reduced ability to inhibit MAC assembly on cell membranes. Publication Abstract from PubMedCD59 is an immunomodulatory cell surface receptor associated with human disease. Despite its importance in complement regulation and bacterial pathogenesis, CD59 remains a challenging therapeutic target. Research to date has focused on antibody or protein-based strategies. Here we present a new approach to target CD59 using macrocyclic peptides with low nanomolar affinity for CD59. Through X-ray crystallographic studies and structure-activity relationship (SAR) studies, we identify key interactions that are essential for binding and activity. We find that the macrocyclic peptide CP-06 adopts a beta-hairpin structure and binds CD59 through an intermolecular beta-sheet, mimicking protein-protein interactions of biologically relevant CD59 interaction partners. We create dimeric and lipidated macrocyclic peptide conjugates as enhanced cell-active CD59 inhibitors and show that these probes can be used to modulate both complement-mediated killing of human cells and lytic activity of bacterial virulence factors. Together, our data provide a starting point for future development of macrocyclic peptides to target CD59 activity in diverse cellular contexts. Macrocyclic Peptide Probes for Immunomodulatory Protein CD59: Potent Modulators of Bacterial Toxin Activity and Antibody-Dependent Cytotoxicity.,Bickel JK, Ahmed AIS, Pidd AB, Morgan RM, McAllister TE, Horrell S, Couves EC, Nagaraj H, Bartlett EJ, El Omari K, Kawamura A, Bubeck D, Tate EW Angew Chem Int Ed Engl. 2025 Apr 24:e202422673. doi: 10.1002/anie.202422673. PMID:40272315[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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